School of Molecular and Cell Biology, Faculty of Science, University of Witwatersrand, Jhb, South Africa.
South African Medical Research Council Vaccines and Infectious Diseases Analytics (VIDA) Research Unit, SA Medical Research Council and Faculty of Health Science, University of the Witwatersrand, Jhb, South Africa; National Institute for Communicable Diseases, Jhb, South Africa.
Vaccine. 2021 Nov 26;39(48):7028-7035. doi: 10.1016/j.vaccine.2021.10.051. Epub 2021 Nov 2.
Live oral rotavirus vaccines have significantly reduced rotavirus-related diarrheal morbidity and mortality globally, but low efficacy of these vaccines is observed in low-income countries where disease burden is highest. The biological basis of rotavirus vaccine failure remains unknown but likely includes both microbial and host factors. We investigated associations between 19 candidate SNPs in the TLR3, TLR7, TLR8, DDX58 and IFIH1 genes that play a role in innate immunity, and seroconversion in Black South African infants after vaccination with Rotarix at 6 and 14 weeks of age. Rotavirus-specific IgA antibody titre was measured by ELISA before each vaccine dose and four weeks after the second dose, and seroconversion was defined as a four-fold or greater increase in IgA antibody titre at 18 weeks of age when compared to pre-vaccine titres. A total of 95/138 individuals seroconverted (68.8%) and seroconversion was significantly affected by birthweight (P = 0.010), pre-vaccine IgA and IgG titres (P = 0.0002 and P = 0.007 respectively). rs2159377 SNP in TLR8 was significantly associated with seroconversion in a univariate allelic model (P = 0.015) and was borderline significant in a multivariable logistic regression adjusted for birthweight and pre-vaccine titres (P = 0.071), although these values did not remain significant after Bonferroni correction. A haplotype of six SNPs on the X chromosome across TLR7 and TLR8, including rs179008 and rs5935438 minor alleles, was significantly associated with seroconversion in a univariate model (P = 0.042), but not in a multivariable model or after Bonferroni correction. Epistatic interaction between rs5743305 in TLR3 and rs55789327 in DDX58 was significantly associated with seroconversion (P = 0.034) but a genetic risk score constructed from all 19 minor alleles was not. Our results suggest that TLR variants may influence IgA antibody production and seroconversion to Rotarix vaccine in South Africans. Host genetic variation contributes to the varying immunogenicity of live oral rotavirus vaccines.
口服轮状病毒活疫苗在全球范围内显著降低了轮状病毒相关腹泻的发病率和死亡率，但在疾病负担最高的低收入国家，这些疫苗的效果较低。轮状病毒疫苗失败的生物学基础尚不清楚，但可能包括微生物和宿主因素。我们研究了在南非黑人婴儿中，19 个候选单核苷酸多态性（SNP）与 TLR3、TLR7、TLR8、DDX58 和 IFIH1 基因之间的关联，这些基因在先天免疫中发挥作用，与接种 Rotarix 后 6 周和 14 周时的血清转化率有关。在每次接种疫苗前和第二次接种疫苗后四周，通过 ELISA 测量轮状病毒特异性 IgA 抗体滴度，当与接种疫苗前的滴度相比，18 周时 IgA 抗体滴度增加 4 倍或以上定义为血清转化率。共有 95/138 人（68.8%）发生血清转化率，血清转化率明显受出生体重（P=0.010）、疫苗前 IgA 和 IgG 滴度（P=0.0002 和 P=0.007）的影响。TLR8 中的 rs2159377 SNP 在单变量等位基因模型中与血清转化率显著相关（P=0.015），在调整出生体重和疫苗前滴度的多变量逻辑回归中呈边缘显著（P=0.071），尽管经过 Bonferroni 校正后这些值不再显著。TLR7 和 TLR8 上 X 染色体上的六个 SNP 的单倍型，包括 rs179008 和 rs5935438 中的次要等位基因，在单变量模型中与血清转化率显著相关（P=0.042），但在多变量模型或 Bonferroni 校正后不相关。TLR3 中的 rs5743305 和 DDX58 中的 rs55789327 之间的上位性相互作用与血清转化率显著相关（P=0.034），但从所有 19 个次要等位基因构建的遗传风险评分没有。我们的结果表明，TLR 变体可能影响南非人对 Rotarix 疫苗的 IgA 抗体产生和血清转化率。宿主遗传变异导致口服活轮状病毒疫苗的免疫原性不同。
